Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes

Drugs, Mar 2018

Introduction To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). Methods A systematic search was conducted using the Medline® and Embase® databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. Results Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates. Conclusions While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine.

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Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes

Drugs Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes Hillel P. Cohen 0 1 2 3 4 5 Andrew Blauvelt 0 1 2 3 4 5 Robert M. Rifkin 0 1 2 3 4 5 Silvio Danese 0 1 2 3 4 5 Sameer B. Gokhale 0 1 2 3 4 5 Gillian Woollett 0 1 2 3 4 5 Hillel P. Cohen 0 1 2 3 4 5 0 Rocky Mountain Cancer Centers , Denver, CO , USA 1 Oregon Medical Research Center , Portland, OR , USA 2 Sandoz Inc. , 100 College Road West, Princeton, NJ 08540 , USA 3 Avalere Health , Washington, DC , USA 4 Novartis Ltd. , Hyderabad , India 5 IBD Center, Humanitas Clinical and Research Hospital , Milan , Italy Introduction To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). Methods A systematic search was conducted using the Medline and Embase databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. Results Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein - medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates. Conclusions While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine. Keypoints Scientific literature (1993 up to 30 June 2017) was reviewed to identify publications that contained primary data on single or multiple switching from reference biological medicines to biosimilars. A total of 90 studies were identified involving seven molecular entities that treated 14 disease indications, and enrolled a total of 14,225 individuals. The great majority of studies did not report differences in safety, efficacy, or immunogenicity after a single switch event compared to patients that were not switched. Only a small number (three) of multiple switch studies have been published to date, but likewise no differences were detected. Overall, the results suggest a low risk of either a safety concern or a loss of efficacy after switching to a biosimilar. 1 Introduction Biological medicines (biologics) are medicines made in living systems. Biosimilars are copies of already licensed biologics (referred to as the reference medicine) that are highly similar, but that are made by different sponsors using independently-derived cell lines and separately-developed manufacturing processes [ 1, 2 ]. Biosimilars can only be approved if a manufacturer demonstrates that there are no clinically meaningful differences in safety, efficacy, and immunogenicity when directly compared with the reference medicine [3]. The experience with the reference medicine, in both preapproval clinical trials and post-approval routine clinical practice of medicine, provides a baseline for the safety and efficacy expected for both reference medicines and their corresponding biosimilars. To date, no new safety or efficacy concerns have been detected in the over 10 years and greater than 700 million days of patient experience with biosimilars [ 4 ]. Nonetheless, concerns have been raised that switching patients from reference medicines to biosimilars, or other structurally-related biologics, may lead to increased immunogenicity and consequential safety problems, or even a loss of efficacy. A review of switching studies reported in the literature is an important first step to confirm or deny any existing pattern that may exist related to biologic switching. Switches occur when patients receive medicines formally designated as biosimilars, but may also occur after manufacturing process changes have occurred, if the process changes lead to structural modifications or changes in the impurit (...truncated)


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Hillel P. Cohen, Andrew Blauvelt, Robert M. Rifkin, Silvio Danese, Sameer B. Gokhale, Gillian Woollett. Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes, Drugs, 2018, pp. 463-478, Volume 78, Issue 4, DOI: 10.1007/s40265-018-0881-y